The ventral medulla oblongata regulates sympathetic efferent activity to the cardiovascular system. Neurons containing substance P (SP) and thyrotropin releasing hormone (TRH) project from the ventral medulla to the spinal cord intermediolateral cell column (IML) (the site of origin of preganglionic sympathetic neurons). Pharmacologic experiments suggest that SP mediates sympathoexcitatory responses elicited from the ventral medulla. The proposed experiments are intended (1) to further elucidate the role of SP and TRH in the ventral medullary regulation of cardiovascular function by studying the cellular location of TRH receptors and sympathetic cardiovascular effects of IML TRH receptor activation, by assessing in vivo the effects of ventral medullary activation on an index of SP and TRH turnover, and by determining the effects of SP and TRH analogs on regional spinal cord and peripheral blood flow; and (2) to provide more complete information on the chemical neuroanatomy of the ventral medulla by studying the origin, and cellular location of terminals and receptors of the tonically active GABAergic innervation of ventral medullary SP and TRH neurons, and to evaluate SP and TRH coexistence in nonserotonergic neurons in the ventral medulla and terminals in the IML. We will use neuroanatomical and neurochemical techniques (neuronal tract tracing, immunocytochemistry, receptor autoradiography, peptide turnover, radioimmunoassay), and in vivo neuropharmacological techniques (CNS injections and monitering of heart rate, blood pressure, and regional blood flow). These studies will provide information on the chemical neuroanatomy and functional role of efferent (SP, TRH) and afferent (GABA) neuronal systems of the ventral medulla. This information is vital to the understanding of CNS control of the cardiovascular system and may enable the design of new therapeutic approaches and drugs to treat and/or prevent cardiovascular diseases.